Cytochrome P450
107
arose. Our modern chemical environment
is less than 200 years old. Nevertheless,
forms such as P4501A1 are found in Fshes
and all mammals. This P450 metabolizes
polycyclic aromatic hydrocarbons, which
can arise from burning organic matter.
Perhaps such forms were Frst produced
during volcanic eras and have persisted to
present times.
Much of the P450-dependent xenobiotic
metabolism serves the purpose of detoxi-
Fcation. Hydroxylated products are more
soluble than the original substrates and
also serve as good substrates for phase
II detoxiFcation enzymes, which conju-
gate these products for easier elimination.
Obviously, this ability is beneFcial to hu-
mans, just as detoxifying xanthotoxin is
beneFcial to the black swallowtail butterfly
larvae. In certain cases, however, prod-
ucts produced by P450 metabolism can be
more toxic than the substrate. ±or exam-
ple, benzo(a)pyrine, a polycyclic aromatic
hydrocarbon in tobacco smoke that also
arises from charbroiling meat, is converted
by P450-dependent biotransformation into
a product that is carcinogenic and may play
a key role in lung cancer. Thus, in certain
instances, products of P450 biotransfor-
mation can be mutagenic or carcinogenic.
The pharmaceutical industry is particu-
larly interested in the roles P450s play in
drug metabolism. This metabolism obvi-
ously contributes to the efFcacy of phar-
maceuticals. In drug metabolism studies
using laboratory animals, inbred strains
are generally used in which all individuals
contain fairly constant levels of different
forms of drug-metabolizing P450s. Hu-
mans are outbred and show considerable
individual variation in drug metabolism.
Each individual can be considered to have
a unique drug-metabolizing proFle in part
because of the person’s individual P450
pattern, which is dependent on genetic
(sex, age) and environmental (nutrition, ex-
posure) factors. The human genome has
revealed genomic evidence for 57 P450s
to date, a mixture of forms metaboliz-
ing endogenous and exogenous substrates.
Of this latter group, six found in human
liver are primary P450s used to study P450
metabolism of potential pharmaceuticals.
In some cases, different forms of P450
metabolize the same chemical substrate
by different reactions, leading to varied
patterns of products from the same drug.
Thus, individual variation in the levels
of different P450s can signiFcantly affect
drug metabolism, particularly in instances
of combined drug therapy. Genetic con-
tributions to individual variations (drug
metabolism polymorphisms) exist within
the human population as a result of varia-
tions in the levels of speciFc forms of P450
or mutations within speciFc enzymes.
Thus, certain individuals, classed as poor
metabolizers for speciFc drugs, do not
c
learthesedrugsasefFc
ient
lyasthegen
-
eral population and experience side effects
reminiscent of drug overdose. A goal of
research in drug metabolism is to develop
noninvasive screening procedures that will
permit estimation of individual P450 pro-
Fles. Thus, individual treatment regimens
could be prescribed providing both health
and economic beneFts to patients.
While the classiFcation of P450s into
two groups as used here is helpful, ances-
tral P450s probably have existed for more
than 3.5 billion years. This longevity sug-
gests that the drug-metabolizing forms of
P450 could play important roles in regu-
lating key endogenous compounds used
in growth, development, and homeosta-
sis. In most cases, no biological connec-
tion between members of the exogenous
substrate–metabolizing class and speciFc
endogenous substrates (e.g. retinoids) has
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